Assessment of candidate immunohistochemical prognostic markers of meningioma recurrence.

Although tumour recurrence is an important and not infrequent event in meningiomas, predictive immunohistochemical markers have not been identified yet. The aim of this study was to address this clinically relevant problem by systematic retrospective analysis of surgically completely resected meningiomas with and without recurrence, including tumour samples from patients who underwent repeat surgeries. Three established immunohistochemical markers of routine pathological meningioma work-up have been assessed: the proliferative marker Ki-67 (clone Mib1), the tumour suppressor gene p53 and progesterone receptor (PR). All these proteins correlate with the tumour WHO grade, however the predictive value regarding recurrence and progression in tumour grade is unknown. One hundred and fourteen surgical specimens of 70 meningioma patients (16 male and 54 female) in a 16 years' interval have been studied. All tumours had apparently complete surgical removal. On Mib1, PR and p53 immunostained sections, the percentage of labelled tumour cells, the staining intensity and the multiplied values of these parameters (the histoscore) was calculated. Results were statistically correlated with tumour WHO grade, (sub)type, recurrence and progression in WHO grade at subsequent biopsies. Our results confirmed previous findings that the WHO grade is directly proportional to Mib1 and p53 and is inversely proportional to the PR immunostain. We have demonstrated that Mib1 and p53 have a significant correlation with and predictive value of relapse/recurrence irrespective of the histological subtype of the same WHO grade. As a quantitative marker, Mib1 has the best correlation with a percentage of labelled cells, whereas p53 with intensity and histoscore. In conclusion, the immunohistochemical panel of PR, p53, Mib1 in parallel with applying standard diagnostic criteria based on H and E stained sections is sufficient and reliable to predict meningioma recurrence in surgically completely resected tumours.

Fusionless posterior hemivertebra resection in a 2-year-old child with 16 years follow-up.

PURPOSE: We present the case of a 2-year-old patient with congenital scoliosis due to a lumbar hemivertebra. The current gold standard treatment of such an abnormality would be hemivertebra resection and short level posterior spinal fusion. However, due to the young age of the patient, we considered that application of a fusionless solution might offer advantages in terms of retaining normal segmental motion and the potential for growth. METHODS: The incarcerated hemivertebra was resected and the facet joints of the neighbouring vertebrae were joined to create a new functional motion segment and correct the kyphoscoliotic deformity. Transpedicular screws were inserted on the convex side in L2 and L3 and a tension band was applied. RESULTS: 16 years after the surgery, the patient was completely pain-free, motion of the lumbar spine was preserved and the physiological curvatures were maintained. CONCLUSION: To our knowledge a fusionless surgical solution for the treatment of a hemivertebra has never been described before. Although this is only a single case, the good result with a long follow-up suggests the technique is worthwhile considering when planning the treatment of a lumbar hemivertebra in very young children.

Expression of invasion-related extracellular matrix molecules in human glioblastoma versus intracerebral lung adenocarcinoma metastasis.

Tumor cell invasion into the surrounding brain tissue is mainly responsible for the failure of radical surgical resection, with tumor recurrence in the form of microdisseminated disease. Extracellular matrix (ECM)-related molecules and their receptors predominantly participate in the invasion process, including cell adhesion to the surrounding microenvironment and cell migration. The extent of infiltration of the healthy brain by malignant tumors strongly depends on the tumor cell type. Malignant gliomas show much more intensive peritumoral invasion than do metastatic tumors. In this study, the mRNA expression of 30 invasion-related molecules (twenty-one ECM components, two related receptors, and seven ECM-related enzymes) was investigated by quantitative reverse transcriptase-polymerase chain reaction. Fresh frozen human tissue samples from glioblastoma (GBM), intracerebral lung adenocarcinoma metastasis, and normal brain were evaluated. Significant differences were established for 24 of the 30 molecules. To confirm our results at the protein level, immunohistochemical analysis of seven molecules was performed (agrin, neurocan, syndecan, versican, matrix metalloproteinase 2 [MMP-2], MMP-9, and hyaluronan). Determining the differences in the levels of invasion-related molecules for tumors of different origins can help to identify the exact molecular mechanisms that facilitate peritumoral infiltration by glioblastoma cells. These results should allow the selection of target molecules for potential chemotherapeutic agents directed against highly invasive malignant gliomas.

Duplication of 7q34 is specific to juvenile pilocytic astrocytomas and a hallmark of cerebellar and optic pathway tumours.

BACKGROUND: Juvenile pilocytic astrocytomas (JPA), a subgroup of low-grade astrocytomas (LGA), are common, heterogeneous and poorly understood subset of brain tumours in children. Chromosomal 7q34 duplication leading to fusion genes formed between KIAA1549 and BRAF and subsequent constitutive activation of BRAF was recently identified in a proportion of LGA, and may be involved in their pathogenesis. Our aim was to investigate additional chromosomal unbalances in LGA and whether incidence of 7q34 duplication is associated with tumour type or location. METHODS AND RESULTS: Using Illumina-Human-Hap300-Duo and 610-Quad high-resolution-SNP-based arrays and quantitative PCR on genes of interest, we investigated 84 paediatric LGA. We demonstrate that 7q34 duplication is specific to sporadic JPA (35 of 53 - 66%) and does not occur in other LGA subtypes (0 of 27) or NF1-associated-JPA (0 of 4). We also establish that it is site specific as it occurs in the majority of cerebellar JPA (24 of 30 - 80%) followed by brainstem, hypothalamic/optic pathway JPA (10 of 16 - 62.5%) and is rare in hemispheric JPA (1 of 7 - 14%). The MAP-kinase pathway, assessed through ERK phosphorylation, was active in all tumours regardless of 7q34 duplication. Gain of function studies performed on hTERT-immortalised astrocytes show that overexpression of wild-type BRAF does not increase cell proliferation or baseline MAPK signalling even if it sensitises cells to EGFR stimulation. CONCLUSIONS AND INTERPRETATION: Our results suggest that variants of JPA might arise from a unique site-restricted progenitor cell where 7q34 duplication, a hallmark of this tumour-type in association to MAPK-kinase pathway activation, potentially plays a site-specific role in their pathogenesis. Importantly, gain of function abnormalities in components of MAP-Kinase signalling are potentially present in all JPA making this tumour amenable to therapeutic targeting of this pathway.

Epidural malignant lymphomas of the spine: collected experiences with epidural malignant lymphomas of the spinal canal and their treatment.

STUDY DESIGN: Retrospective study of 13 patients treated by the authors. OBJECTIVE: To examine the course of the disease of malignant lymphoma (ML) presenting in the epidural area of the spine. SETTING: Department of Neurosurgery, Third Department of Internal Medicine, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary. SUBJECTS AND METHODS: The epidural presentation in eight patients was heralded by motor signs (paraparesis and plegia), in one by a lesion of the posterior columns of the spinal cord (ataxia), and in three by pain. One patient was free of complaints and symptoms. The affected epidural area was diagnosed previously by myelography and computerized tomography (CT), and later by magnetic resonance (MR), over the course of which the location was verified as thoracic in eight patients, cervical in one, and lumbar in four. The authors recommended surgical intervention in 9 out of 13 cases, in seven cases of Hodgkin's and six cases of non-Hodgkin's lymphoma. Seven patients were treated for recognized manifestations of malignant lymphoma while six were diagnosed by intraoperative-histological examination. RESULTS AND CONCLUSION: The decompression operations for tumors resulted in limited improvement in seven patients (reduction in pain and return of ability to walk). Four patients were not operated on, two of which had significant improvement in their neurological symptoms. Paraparesis remained unchanged in one patient. One patient remained symptom-free. The authors emphasize the importance of interdisciplinary consultation and weighing individual priorities in the indications for operation on epidural ML.

Bilateral epilepsy surgery in a 4-year-old child.

OBJECTIVE: Reports on bilateral epilepsy surgical interventions are anecdotal because of the possible neurological deficits caused by them. METHODS: We report on a four-year-old amaurotic child with catastrophic epilepsy due to bilateral occipital cortical dysplasia. After video-EEG monitoring and intraoperative electrocorticography he underwent a two-step bilateral occipital lobectomy. RESULTS: The first resection resulted in only temporary seizure cessation; however, he became seizure-free after the second operation (follow-up: 20 months). CONCLUSION: Patients with catastrophic epilepsy due to bilateral epileptogenic lesions but without a high risk of additional postsurgical deficit may be good candidates for epilepsy surgery.

Circadian clock-regulated expression of phytochrome and cryptochrome genes in Arabidopsis.

Many physiological and biochemical processes in plants exhibit endogenous rhythms with a period of about 24 h. Endogenous oscillators called circadian clocks regulate these rhythms. The circadian clocks are synchronized to the periodic environmental changes (e.g. day/night cycles) by specific stimuli; among these, the most important is the light. Photoreceptors, phytochromes, and cryptochromes are involved in setting the clock by transducing the light signal to the central oscillator. In this work, we analyzed the spatial, temporal, and long-term light-regulated expression patterns of the Arabidopsis phytochrome (PHYA to PHYE) and cryptochrome (CRY1 and CRY2) promoters fused to the luciferase (LUC(+)) reporter gene. The results revealed new details of the tissue-specific expression and light regulation of the PHYC and CRY1 and 2 promoters. More importantly, the data obtained demonstrate that the activities of the promoter::LUC(+) constructs, with the exception of PHYC::LUC(+), display circadian oscillations under constant conditions. In addition, it is shown by measuring the mRNA abundance of PHY and CRY genes under constant light conditions that the circadian control is also maintained at the level of mRNA accumulation. These observations indicate that the plant circadian clock controls the expression of these photoreceptors, revealing the formation of a new regulatory loop that could modulate gating and resetting of the circadian clock.

Conditional circadian regulation of PHYTOCHROME A gene expression.

The phytochrome photoreceptors and the circadian clock control many of the same developmental processes, in all organs and throughout the growth of Arabidopsis plants. Phytochrome A (phyA) provides light input signals to entrain the circadian clock. The clock is known to rhythmically regulate its light input pathway, so we tested rhythmic regulation of phyA, using transgenic plants carrying a PHYA promoter fusion to the luciferase reporter (PHYA:LUC). We provide the first images of LUC activity with subcellular resolution in intact tissue. PHYA transcription and the accumulation of all three PHYA mRNAs were indeed clock controlled. PHYA is expressed throughout the seedling, so we tested whether circadian rhythms were observed in all PHYA-expressing organs and whether the rhythms were autonomously controlled by each organ. In contrast to our previous results using other clock controlled genes, the rhythmic pattern of PHYA expression varied markedly among isolated organs and between isolated organs and intact plants. High-amplitude rhythms were maintained for many days in isolated leaves in darkness, whereas the leaves of intact plants rapidly lost rhythmicity. Wounding the leaves of intact plants had no effect. The rhythmic pattern of PHYA expression is not organ autonomous but depends upon the physical continuity or isolation of the rhythmic tissues, consistent with the presence of a transmitted signal that controls the overt expression of circadian rhythms without necessarily affecting the underlying clock. A circadian system might be present in most, if not all, plant cells, but its effect on intracellular rhythms can be controlled by supracellular signaling.

[Surgically treatable epilepsy--a review]. / Mútéttel gyógyítható epilepszia--összefoglaló tanulmány.

20-25% of epileptic patients do not become seizure free on adequate drug therapy. In 25-50% of patients with intractable epilepsy, the brain area responsible for seizures is well localizable and does not involve eloquent regions. In these patients, the surgical excision of the epileptic focus may lead to relief from seizures. In Hungary, there may be 5-6000 patients who needs an epilepsy surgery, but till now only 200 patients with chronic epilepsy underwent a surgical procedure. In the surgically remediable epilepsies, the operation is not a "ultima ratio". Concerning these syndromes, if 2-3 adequate antiepileptic drugs do not lead to seizure freedom within 1-3 years after the epilepsy onset, then a presurgical evaluation is necessary. The most common surgically remediable epilepsy is the temporal lobe epilepsy in which 60-90% of drug-resistant patients could be surgically cured. In lesional neocortical epilepsies 50-80% of patients become postoperatively seizure free. In childhood hemispheric epilepsies, the surgery could lead to seizure freedom in 70-80% of patients. The basic tools of the presurgical evaluation are the detailed history, the high resolution-MRI, the video-EEG monitoring, and the neuropsychological assessment. These investigation methods are usually enough to evaluate the necessity of the surgery and the postoperative outcome as well as to plan the localization and the extension of the resection. In some cases, ictal SPECT, PET, or video-EEG monitoring with intracranial electrodes could also be necessary in order to localize the epileptic focus.

The response regulator ARR2: a pollen-specific transcription factor involved in the expression of nuclear genes for components of mitochondrial complex I in Arabidopsis.

Two-component signal systems regulate a variety of cellular activities. They involve at least two common signalling molecules: a signal-sensing kinase and a response regulator that mediates the output response. Multistep systems also require proteins containing phosphotransfer domains. Here we report that the response regulator ARR2 from Arabidopsis is predominantly expressed in pollen and is localized in the nuclear compartment of the plant cell. Furthermore, ARR2 is transcriptionally active in yeast and binds to the promoters of nuclear genes for several components of mitochondrial respiratory chain complex I (nCI) from Arabidopsis. The nuclear nCI genes are up-regulated in pollen during spermatogenesis. The transcription factor functions of ARR2 are mediated by its C-terminal output domain. Our data identify ARR2 as the first eukaryotic response regulator which functions as a transcription factor at a known promoter sequence. Yeast two-hybrid analysis and in vitro interaction studies suggest that ARR2 very probably forms part of a multistep two-component signalling mechanism that includes HPt proteins like AHP1 or AHP2. These findings point to an as yet unidentified signal transduction system that may regulate aspects of floral and mitochondrial gene expression.

Temporary cerebral histic hypoxia in simulated microgravity.

The authors determined in their previous examinations that the vertical component of diagonal optokinetic nystagmus (DOKN) decreases considerably more in the conditions of hypoxia and antiorthostatic posture than does the horizontal component. Relying on these findings, they reasoned that the tectal and pretectal gaze centers, which organize vertical eye movement, are more sensitive to both hypoxia and antiorthostatic posture than is the pontine gaze center, which directs horizontal eye movement. In their present examinations, the authors sought to discover how cranial shifting of body fluids alters the DOKN and cardiopulmonary dynamics. They established that, at-30-degree antiorthostatic posture during 3 hours' loading, the diminution of pulse rate and systolic blood pressure is accompanied by continuous enhancement of diastolic blood pressure, diminishment of the carbonometric value, and augmentation of respiratory rate. The disturbances of DOKN, which mimicked previous similar findings under conditions of hypoxia and antiorthostatic posture, may be caused by the hypocapnia that is induced by antiorthostatic posture and that produces histic hypoxia. However, hypocapnia does not exclude the possibility of cerebrovascular injury, which was detected during animal experiments in microgravity or in simulated microgravity. To resolve this issue ultimately, further investigations are necessary.

Photocontrol of subcellular partitioning of phytochrome-B:GFP fusion protein in tobacco seedlings.

Photomorphogenesis of higher plants is regulated by photoreceptors including the red/far-red light-absorbing phytochromes, blue-UV/A sensing cryptochromes and as yet uncharacterized UV/B receptors. Specific phototransduction pathways that are controlled by either individual or interacting photoreceptors mediate regulation. Phytochrome B (phyB) is the major red light-sensing photoreceptor. Phototransduction mediated by this light sensor has been shown to include light-dependent nuclear import and interaction of phyB with transcription factor-like proteins in the nucleus. Here we report that nuclear import of phyB and physiological responses regulated by this photoreceptor exhibit very similar wavelength- and fluence rate-dependence. Nuclear import of phyB is insensitive to single red, blue and far-red light pulses. It is induced by continuous red light and to a lesser extent by continuous blue light, whereas far-red light is completely ineffective. The data presented indicate that light-dependent partitioning of phyB exhibits features characteristic of blue light responsiveness amplification, a phenomenon that is thought to be mediated by interaction of phyB with CRY1.

[Neuronavigation in pediatric neurosurgery]. / Neuronavigáció a gyermek-idegsebészetben.

The precise orientation in the intracranial space is essential for the minimal invasive neurosurgical interventions. The CT and MR based neuro-navigation permits small, targeted exposures on the skull, and intraoperatively gives exact graphic-interactive guidance to the targeted intracranial lesions. The use of neuro-navigation can shorten the time of surgery and diminish the surgical mortality and morbidity. The favourable experiences of the first 21 neuro-navigation aided operations in pediatric patients performed in the National Institute of Neurosurgery (Budapest, Hungary) with the Vector Vision Neuro-navigation System (BrainLAB Gmbh, Germany) are discussed.

[Chiari I. malformation, a new childhood disease?]. / Chiari I. malformáció, egy "új" gyermekbetegség?

From July 1, 1994 to July 1, 1997 a total of 17 children with Chiari I malformation diagnosed by MRI was seen in our hospital. Six of them underwent craniocervical decompression and tonsilar resection. The major complaints of all these children were gait ataxia and persisting (longer than 6 month) headache, and one child had acutely presenting vertigo and problem of swallowing. The MRI showed that in all cases the tonsils were displaced below the level of CI. Hydrocephalus or syrinx was not seen. At surgery the tonsils were resected. All the patients can be considered cured and symptom free at an average follow up of 13 month.

[Neuroendoscopic removal of a colloid cyst of the third ventricle]. / Harmadik kamrai kolloid cysta neuroendoszkópos eltíavoltása.

The removal of the benign and only slightly symptomatic but by virtue of their localization potentially fatal lesions is a challenge for the neurosurgeons. Such cases demand a therapy without any postoperative morbidity. The neuroendoscopy meets these requirements and proves to be effective in more and more fields of the art. This article reports a case when colloid cyst was resected entirely by use of a neuroendoscope, firstly in Hungary.

Effect of microgravitation on the human equilibrium.

The 38-year period of human space exploration has gained for us a lot of experience in the problem of space motion sickness. The authors collected some causes of space sickness from the literature and from their research results. We collaborated with the Soviet-Russian space researchers and elaborated those vestibular research methods that were carried out by human space missions in the Soviet-Russian space station, on Earth, and after flight: spontaneous eye movement, foveal and peripheral optokinetic nystagmus, and vestibular stimulation. Using an earthly model of the effect of microgravitation on the human body, we tried to provide explanations of the origin of space motion sickness.

The circadian clock controls the expression pattern of the circadian input photoreceptor, phytochrome B.

Developmental and physiological responses are regulated by light throughout the entire life cycle of higher plants. To sense changes in the light environment, plants have developed various photoreceptors, including the red/far-red light-absorbing phytochromes and blue light-absorbing cryptochromes. A wide variety of physiological responses, including most light responses, also are modulated by circadian rhythms that are generated by an endogenous oscillator, the circadian clock. To provide information on local time, circadian clocks are synchronized and entrained by environmental time cues, of which light is among the most important. Light-driven entrainment of the Arabidopsis circadian clock has been shown to be mediated by phytochrome A (phyA), phytochrome B (phyB), and cryptochromes 1 and 2, thus affirming the roles of these photoreceptors as input regulators to the plant circadian clock. Here we show that the expression of PHYB::LUC reporter genes containing the promoter and 5' untranslated region of the tobacco NtPHYB1 or Arabidopsis AtPHYB genes fused to the luciferase (LUC) gene exhibit robust circadian oscillations in transgenic plants. We demonstrate that the abundance of PHYB RNA retains this circadian regulation and use a PHYB::Luc fusion protein to show that the rate of PHYB synthesis is also rhythmic. The abundance of bulk PHYB protein, however, exhibits only weak circadian rhythmicity, if any. These data suggest that photoreceptor gene expression patterns may be significant in the daily regulation of plant physiology and indicate an unexpectedly intimate relationship between the components of the input pathway and the putative circadian clock mechanism in higher plants.

Light quality-dependent nuclear import of the plant photoreceptors phytochrome A and B

The phytochrome (phy) family of plant photoreceptors controls various aspects of photomorphogenesis. Overexpression of rice phyA-green fluorescent protein (GFP) and tobacco phyB-GFP fusion proteins in tobacco results in functional photoreceptors. phyA-GFP and phyB-GFP are localized in the cytosol of dark-adapted plants. In our experiments, red light treatment led to nuclear translocation of phyA-GFP and phyB-GFP, albeit with different kinetics. Red light-induced nuclear import of phyB-GFP, but not that of phyA-GFP, was inhibited by far-red light. Far-red light alone only induced nuclear translocation of phyA-GFP. These observations indicate that nuclear import of phyA-GFP is controlled by a very low fluence response, whereas translocation of phyB-GFP is regulated by a low fluence response of phytochrome. Thus, light-regulated nucleocytoplasmic partitioning of phyA and phyB is a major step in phytochrome signaling.

Antiorthostatic posture as an earth model of the effect of microgravity on the human body.

We examined the horizontal and vertical component of diagonal optokinetic nystagmus (DOKN) in sitting posture and in the last 15 minutes of antiorthostatic posture at -30 degrees lasting 3 hours. The antiorthostatic posture is suited to the earthy model of the fluid shifting observed in microgravity. We found that the frequency of the vertical component of DOKN is rarer in antiorthostatic posture than in sitting posture. Moreover, the amplitude of the vertical component of DOKN is lower in antiorthostatic posture than is the amplitude of the horizontal component. According to our examinations, we suppose that the frequency and amplitude of vertical OKN are directed by different cerebral structures. Furthermore, we found that the heart rate becomes slower and the diastolic pressure is augmented after antiorthostatic posture and visual stimulation.